A novel in-frame deletion in MEN1 (p.Ala416del) causes familial multiple endocrine neoplasia type 1 with an aggressive phenotype and unexpected inheritance pattern

Abstract

The present study describes a family with multiple endocrine neoplasia type 1 (MEN1) caused by a previously undescribed in-frame deletion c.1246-1248delGCC (Ala416del) in the MEN1 gene. Evidence for the pathogenic character of this mutation, which triggers an aggressive clinical outcome, is demonstrated. Aggregation analysis in the tested family was strongly suggestive of causality of the detected mutation. This was supported by the analysis of LOH (loss of heterozygosity) in tumor-derived DNA and by computational analysis of the functional and structural implications of the mutation. Different phenotypic characteristics were identified among family members, which is typical for MEN1. Additionally, an unexpected disease inheritance pattern was observed in this kindred, in which either all or none of the siblings of one branch inherited the disease.